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Therapeutics for leishmaniasis: from screening to the study of mechanisms of action, a contribution to the discovery of new antileishmanial molecules

Grant number: 20/04415-4
Support type:Regular Research Grants
Duration: August 01, 2021 - July 31, 2023
Field of knowledge:Biological Sciences - Biochemistry - Biochemistry of Microorganisms
Principal researcher:Marcia Aparecida Silva Graminha
Grantee:Marcia Aparecida Silva Graminha
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Assoc. researchers: Andrew Philip Thomas

Abstract

Leishmaniasis is a pathogenic disease found throughout the world caused by protozoan parasites of the Leishmania genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance to them makes providing new therapeutic alternatives urgent. We have been studying a new furoxan molecule, 14e, which present efficacy in diminish the parasite load in L. infantum infected hamsters. The parasitemia reduction might be related to inhibition of a parasitic protease, the cysteine protease B, release of NO and interference in the parasite Ca2+ homeostasis. Although we did not observe neither side effects nor elevation of hepatic/ renal biomarkers in the plasma levels, 14e presented low solubility, which turns difficult its use in a possible oral administration. Thus, rational chemical modifications has been made in order to change its solubility and keep its capacity to inhibit CPB, an important virulence factor of Leishmania. These data strength our already existent collaboration with the groups LAPDESF from FCF-UNESP and calcium signaling from Rutgers University in order to advance in the comprehension of the antileishmanial properties of the new synthetic derivatives as well as to evaluate their NO-donor potential and protease inhibition. Moreover, another goal of this project is to continue our screening program to search for new antileishmanial agents from natural sources or synthetic molecules, including other research groups to our collaboration network. This proposal is multidisciplinar and bears different areas including molecular genetics and biochemistry, relying on the efforts of students and researchers and allowing exchange of personnel among these groups. (AU)

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